Current status of chimeric antigen receptor therapy for haematological malignancies

Abstract

SummaryThe field of adoptive cell transfer includes chimeric antigen receptor (CAR) engineered T cells, constructs that emerged from basic research into principles of immunology and have transformed into clinically effective therapies for haematological malignancies. T cells engineered to express these artificial receptors hold great promise, but also carry significant risk. While permanent genetic modification of mature T cells appears safe, modulating their in vivo function is difficult, partly because the robust response can trigger other arms of the immune system. Suicide systems and toxicity management with cytokine blockade or signal transduction modulators have emerged as a new frontier in this field, a far cry from early problems getting CAR T cells to work at all. Currently, clinical trials in patients with relapsed or refractory B cell malignancies treated with CD19-specific CAR T cells have induced durable remissions in adults and children. Results from these trials indicate that more work needs to be done to understand biomarkers of efficacy, the role of T cell persistence and how to integrate this care into standard practice. Cell therapy will not be a 'one size fits all' class of medicine, and here we will discuss the development of this therapy and important questions for its future.

Engineering HIV-Resistant, Anti-HIV Chimeric Antigen Receptor T Cells

“…Additionally, even with the most studied CD19CAR, it is not yet clear which in vitro assays best predict clinical success. 26 Therefore, we hesitate to make definitive claims regarding the relative performance of candidate HIVCARs derived from the alternative bNAb scFvs. Given the propensity of HIV to mutate to evade specific pressures, it seems prudent to develop multiple HIVCARs that target different epitopes and could be used in combination to treat HIV.…”

“…24,25 Over the last decade, major advances have been made in engineering human T cells via introduction of chimeric antigen receptors (CARs) to enable specific lysis of pathogenic targets. [26][27][28][29] Because CAR T cell activity is MHC-independent, potent, and enforced by expression of an engineered gene cassette, anti-HIV CAR T cells might overcome the limitations of autologous CTLs. In fact, although the major clinical success has occurred in treatment of select lymphoid malignancies, one of the earliest CAR T cell therapies to reach clinical trials was designed for the treatment of HIV.…”

Use of Chimeric Antigen Receptor T Cells in Allogeneic Hematopoietic Stem Cell Transplantation

“…However, CAR-T cells only can survive in the body for a short period of time, some of the patients relapsed quickly [21,22]. In our center, a total of 14 patients with refractory/relapsed B-ALL were treated with CD19-CAR-T cells.…”

CAR-T Cells and Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

“…Altogether, approximately 40-90% of patients with refractory/relapsed ALL can reach complete molecular or cellular remission through treatment with CAR-T cells; however, because CAR-T cells survived in the body for only a short time, some of the patients relapsed quickly, which may be related to the different in the costimulatory molecular or vectors used, or variation in the disease burden across treated individuals [36,37] (Table 1). Thus, other treatments should be performed to improve outcomes in the treatment of refractory/relapsed ALL.…”